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Abstract

Background

Chronic knee pain is a common and disabling condition in people over 50 years of age,
with knee joint osteoarthritis being a major cause. Acupuncture is a popular form
of complementary and alternative medicine for treating pain and dysfunction associated
with musculoskeletal conditions. This pragmatic Zelen-design randomised controlled
trial is investigating the efficacy and cost-effectiveness of needle and laser acupuncture,
administered by medical practitioners, in people with chronic knee pain.

Methods/Design

Two hundred and eighty two people aged over 50 years with chronic knee pain have been
recruited from metropolitan Melbourne and regional Victoria, Australia. Participants
originally consented to participate in a longitudinal natural history study but were
then covertly randomised into one of four treatment groups. One group continued as
originally consented (ie natural history group) and received no acupuncture treatment.
The other three were treatment groups: i) laser acupuncture, ii) sham laser or, iii)
needle acupuncture. Acupuncture treatments used a combined Western and Traditional
Chinese Medicine style, were delivered by general practitioners and comprised 8–12
visits over 12 weeks. Follow-up is currently ongoing. The primary outcomes are pain
measured by an 11-point numeric rating scale (NRS) and self-reported physical function
measured by the Western Ontario and McMaster (WOMAC) Universities Osteoarthritis Index
subscale at the completion of treatment at 12 weeks. Secondary outcomes include quality
of life, global rating of change scores and additional measures of pain (other NRS
and WOMAC subscale) and physical function (NRS). Additional parameters include a range
of psychosocial measures in order to evaluate potential relationships with acupuncture
treatment outcomes. Relative cost-effectiveness will be determined from health service
usage and outcome data. Follow-up assessments will also occur at 12 months.

Discussion

The findings from this study will help determine whether laser and/or needle acupuncture
is efficacious, and cost-effective, in the management of chronic knee pain in older
people.

Trial registration

Background

Chronic knee pain is a common and disabling condition, particularly in people over
50 years of age
[1,2]. Knee joint osteoarthritis (OA) is a major cause of knee pain and results in loss
of functional independence, psychological impairment and a reduction in the overall
quality-of-life of affected individuals. In addition to the personal burden of knee
OA, there are substantial direct and indirect health care costs particularly in terms
of employment status, productivity and joint replacement surgery, making knee OA a
substantial public health problem.

Management of knee OA is primarily focused on treating the pain and disability associated
with the condition, with non-pharmacological therapies considered the cornerstone
of treatment
[3]. Acupuncture is a popular treatment for pain and dysfunction associated with musculoskeletal
conditions. A study of 350 rheumatology patients in the United Kingdom revealed that
61% of those with OA had used acupuncture
[4]. In clinical practice, a range of health professionals administer or refer patients
for acupuncture. In Australia, acupuncture by medical practitioners has been established
for 40 years and has gained widespread patient acceptance in the community. We have
found that over 80% of surveyed general medical practitioners referred patients for
acupuncture
[5] and that they generally consider acupuncture to be highly effective and safe
[6]. Amongst all complementary and alternative medicine modalities, acupuncture is associated
with the highest average annualised expenditure
[7]. Thus research to determine its efficacy and cost-effectiveness is warranted.

Acupuncture traditionally involves the insertion of fine needles into specific points
of the body. According to the ancient philosophy of traditional Chinese acupuncture,
energy circulates in 12’meridians’ located throughout the body. Pain or ill health
will result if the meridian energy circulation is blocked. Stimulating the appropriate
combination of meridian acupuncture points in the body can restore energy circulation,
health, and balance
[8]. From a Western medicine perspective, acupuncture is a technique of peripheral sensory
stimulation (through activation of peripheral A-delta and C fibres) applied at acupuncture
points and/or trigger points that can activate central nervous system pain pathways,
release specific pain relieving substances as well as reduce muscle and sympathetic
nervous system tonicity
[9,10].

In recent years there has been a substantial increase in the number of randomised
controlled trials (RCTs) investigating the efficacy of needle acupuncture for chronic
knee pain. A recent meta-analysis concluded that while placebo-controlled trials show
statistically significant benefits for pain, the benefits are small and unlikely to
be clinically relevant
[8]. Waiting list-controlled trials however suggest statistically significant and clinically
relevant benefits, which may be due to expectation or placebo effects. Accordingly,
well-designed rigorous RCTs are needed that control for both placebo and expectation
effects in order to evaluate the efficacy of acupuncture for chronic knee pain.

Although acupuncture has been traditionally administered with needles, the use of
laser acupuncture has increased because of its pain-free nature and minimal adverse
effects
[11]. Laser acupuncture involves the application of low-level laser, which is a form of
electromagnetic radiation in the visible or infrared region of the light spectrum.
These laser devices are manufactured with such low energy densities that photo-chemical
changes are elicited without photo-thermal effects. Within these ranges, various energy
levels and wavelengths can be used depending on the tissue penetration required. In
laser acupuncture, the beam of light generated is applied to the skin at acupuncture
points and/or trigger points, similar to the application of needles.

Laser acupuncture effects are thought to alter peripheral afferent nerve stimulation,
modulating spinal cord afferent input on second order neurons and enhancing peripheral
endogenous opioid analgesia
[12] as well as acting via centrally mediated mechanisms. Laser also has effects at the
local cellular and tissue level
[13] with evidence of modulation of inflammatory processes
[14] varying according to laser dosage
[15].

In contrast to needle acupuncture, the efficacy of laser acupuncture has been less
well studied in the management of chronic knee pain. In general, RCTs have used small
sample sizes and variable laser dosages in terms of wavelength, total energy, application
sites and number of treatments. In a meta-analysis of eight trials published up until
2006 investigating the short-term efficacy (within 4 weeks) of laser therapy for knee
OA, statistically and potentially clinically significant pain-relieving benefits over
placebo were found
[11]. The effect was greater when only trials evaluating an optimal dosage and administration
were included. Since this meta-analysis, two other small studies have been published
providing further support for the use of laser acupuncture in chronic knee pain
[16,17].

It is not clear whether differences in efficacy exist between laser and needle acupuncture
given that there are no direct head-to-head comparisons of needle and laser acupuncture
for chronic knee pain., However, in a systematic review, laser but not needle acupuncture
offered statistically and clinically significant short-term pain relief over placebo
[11]. Similarly, a meta-analysis found that treatment with laser acupuncture had better
pain outcomes in the medium-term, although not short-term, than treatment with needle
acupuncture in people with non-specific neck pain
[18]. These studies suggest that laser acupuncture may be at least as effective, if not
more effective, than needle acupuncture.

It is apparent that there is a need for further evaluation of acupuncture in the management
of chronic knee pain. This is highlighted by discrepancies in recommendations by clinical
guidelines – the Osteoarthritis Research Society International currently recommend
acupuncture
[3], the United Kingdom NICE clinical guidelines could not give a firm recommendation
due to insufficient evidence
[19] and the American College of Rheumatology
[20] conditionally recommend acupuncture but only for patients with moderate to severe
pain who are candidates for joint replacement but are unwilling/unable to have surgery.
Furthermore, there is limited information about the maintenance of acupuncture effects
with no studies reporting a follow-up longer than three months.

In designing appropriate clinical trials, a methodological concern in acupuncture
trials has been the difficulty in having a true placebo control group given pre-existing
participant expectations, particularly where the treatment itself is multidimensional
involving therapist-patient interaction as well as an intervention
[21]. A meta-analysis has confirmed a significant placebo effect for the treatment of
pain in knee OA that varies in size depending on the intervention
[22]. For acupuncture, the placebo effect size (mean 0.71 (95% confidence interval 0.53,
0.90)) was higher than the overall effect size for all placebo treatments (0.51 (0.46,
0.55)). As with many treatments, higher patient expectation has been shown to be associated
with greater improvements following acupuncture treatment. A pooled analysis of four
clinical trials of acupuncture found that after completion of treatment, the odds
ratio for response between patients considering acupuncture an effective or highly
effective therapy and patients who were more sceptical was 1.67 (95% confidence interval
1.20-2.32)
[23]. The use of “sham needle” acupuncture as a placebo control, whereby needling is performed
superficially or at non-acupuncture sites, is controversial given that such a procedure
may still produce biological responses and hence may not be truly placebo. Blinding
of clinicians administering needle acupuncture is also problematic. Such methodological
difficulties can be overcome in trials of laser acupuncture as it is possible to successfully
blind both participants and clinicians by using specially designed laser machines
[24].

First described by Zelen in the New England Journal of Medicine in 1979
[25], Zelen design trials are a means of reducing bias by minimizing participant expectations
in a treatment trial where the knowledge of the intervention itself may influence
the study outcome (Hawthorne effect) in the control group. This is done by enrolling
participants into an observational study but covertly randomising participants following
their recruitment into a treatment trial (post-randomised consent). The control group
remains unaware of the treatment being evaluated
[26]. Such a design has been used successfully in a study comparing a physiotherapy treatment
of exercise and knee taping to standard non-physiotherapy treatment in people with
predominant patellofemoral OA
[27]. A potential disadvantage of the Zelen design can be a higher crossover rate than
a usual RCT which may dilute treatment effects in an intention-to-treat analysis.
However, a review of 58 RCTs using the Zelen design found that while most trials (n = 41)
experienced some crossover from one group to the other (median crossover = 8.9%, interquartile
range 2.6% to 15%) the rate was usually within acceptable limits
[26].

Thus, we are currently conducting a Zelen design RCT to investigate the efficacy of
needle and laser acupuncture administered by experienced medical acupuncturists in
people with chronic knee pain and to evaluate maintenance of effects over the longer
term. We will also evaluate the cost-effectiveness of needle and laser acupuncture,
as well as explore whether psychosocial measures are associated with changes in pain,
physical function and health-related quality of life following acupuncture treatment.
This paper describes the protocol for this ongoing trial.

H5: Laser, sham laser and needle acupuncture will result in significantly greater
improvements in pain (as measured overall via NRS) and physical function (as measured
via WOMAC) than no treatment at 12 months, while laser acupuncture will result in
significantly greater improvements than needle acupuncture.

H6: Laser, sham laser and needle acupuncture will result in significantly greater
improvements in pain (as measured on standing and walking via NRS and by WOMAC), physical
function (as measured via NRS) and health-related quality of life than no treatment
at 12 weeks and 12 months.

H7: Laser acupuncture will result in significantly greater improvements in pain (as
measured on standing and walking via NRS and by WOMAC), physical function (as measured
via NRS) and health-related quality of life than needle acupuncture at 12 weeks and
12 months.

H8: A greater proportion of people receiving laser, sham laser and needle acupuncture
will report global overall improvements compared to no treatment at 12 weeks and 12 months.

Methods/Design

Trial design

Participants

A total of 282 men and women with chronic knee pain have been recruited from the community
in metropolitan Melbourne and regional Victoria, Australia. A number of recruitment
strategies were used including (i) advertisements in local clubs, community centres,
newspapers, Arthritis Australia and University websites, University staff newsletters,
radio, television, and a social networking site; (ii) placement of brochures and study
posters in medical and physiotherapy clinics; and (iii) presentations about knee OA
in the local community by the researchers.

People were eligible to participate if they (i) were aged >50 years; (ii) had a history
of knee pain of >3 months duration; (iii) reported knee pain on most days of the past
month; (iv) reported an average knee pain severity over the past month of ≥ 4 out
of 10 on an 11-point NRS and; (v) reported morning knee stiffness of <30 minutes duration.

Exclusion criteria included: (i) history of any systemic arthritic condition; (ii)
history of knee arthroplasty on the most painful knee; (iii) wait-listed for any knee
surgery for either knee; (iv) history of any knee surgery in previous 6 months; (v)
any other condition affecting lower limb function (eg trauma, malignancy, neurological
condition); (vi) history of any knee injection in past 6 months (eg cortisone, hyaluronic
acid); (vii) current use of oral or injectable anticoagulant medication; (viii) use
of acupuncture in past 12 months; (ix) any bleeding disorder; (x) allergy to light;
(xi) referral to pain clinic or use of morphine or pethadine within past 6 months;
(xii) any other medical condition precluding participation in the trial (eg kidney
or liver disease, deep vein thrombosis); (xiii) knee pain subject to compensation
claim or; (xiv) unable to give written informed consent.

Although both knees could undergo treatment as part of the project, only the most
symptomatic knee as nominated by the participant at enrolment was evaluated.

Procedure

Figure
1 depicts the trial protocol. Eligibility of prospective participants was determined
over the telephone by an investigator (MK) not involved in assessment or treatment
of participants. Ethical approval was obtained from the University of Melbourne Human
Research Ethics Committee (HREC No. 0931840). All participants provided written informed
consent. Initially, all participants consented to participate in a longitudinal observational
natural history study of chronic knee pain, involving assessments at baseline, 12 weeks
and 12 months. All assessments, comprised solely of questionnaires, are completed
by participants at home and mailed back to the University of Melbourne, where data
is entered by a blinded assessor (MK).

Upon receipt of completed baseline questionnaires, an investigator (KN) accessed the
computerised covert randomisation schedule to reveal whether the participant was allocated
either (i) laser acupuncture (could be either real laser or sham laser but the investigator
and participant are blinded to this information); (ii) needle acupuncture or; (iii)
no treatment (control group). Participants randomised into the no treatment arm continue
as consented in the natural history observational cohort for the 12 month duration
of the study and did not undergo (or are made aware of) any intervention as part of
the trial. Participants randomised to receive either laser or needle acupuncture were
telephoned by an investigator (KN) and offered the opportunity to undergo the allocated
intervention and contribute their data to the trial. Participants allocated to the
laser groups were informed they may receive either real laser or sham laser and that
this has been randomly pre-determined and would not be revealed to them until the
completion of the 12 month assessments. Participants willing to participate in the
intervention provided informed consent to do so at this point. Participants who choose
not to participate in the intervention continued as initially consented in the natural
history observational cohort for 12 months, however their data will be analysed as
per intention-to-treat.

Participants who were randomised to receive acupuncture had treatment visits arranged
with a project general practitioner (GP) for treatment over 12 weeks. All study participants,
including those allocated to the no treatment group and those who were randomised
to receive treatment but declined to do so, undergo re-assessment at 12 weeks and
again at 12 months.

Randomisation and allocation concealment

The randomisation schedule was prepared by the study biostatistician (AF). All eligible
participants were consecutively randomised into either the (i) real laser acupuncture;
(ii) sham laser acupuncture; (iii) needle acupuncture or; (iv) no treatment group.
Allocation was randomised within random permuted blocks of six to twelve generated
a priori and stratified according to treating GP so that all GPs delivered approximately
equal numbers in each acupuncture group to control for therapist variation. An electronic
password-protected spreadsheet that contained concealed acupuncture group allocation
was prepared by a researcher (BM) with no other involvement in the study, and held
by an investigator (MP) not involved in recruitment, assessment or treatment. The
patient code numbers for the randomised laser treatment arms were entered into the
study laser machines by an independent biomedical engineer, in order to permit blinding
of both the treating GPs and the participants.

Blinding

Laser and sham laser participants were blinded to treatment allocation, as were the
GPs administering laser and sham laser acupuncture, as the same machine provided both
interventions and the participant code (entered by the GP) determined whether the
machine actually outputted laser or not
[24]. Participants in the no treatment group are unaware that the treatment groups exist
and that their data will be used for comparison (despite having consented to their
longitudinal data being used for other unspecified research questions as determined
by the researchers). Only the participants undergoing needle acupuncture and the GP
provider were unblinded to their treatment group allocation.

Interventions

This trial employed a combined Western and Traditional Chinese Medicine style of acupuncture,
utilizing standardised acupuncture points. Such an approach reflects Australian medical
acupuncture training and clinical practice. Participants were treated by experienced
GPs who are also members of the Australian Medical Acupuncture College. These GPs
have completed a standardised University-delivered acupuncture training course, undertaken
formal accreditation by examination and a minimum period of supervised clinical experience,
and are registered as medical practitioner acupuncturists by the Medical Board of
Victoria. Medical acupuncturists were selected for this study to minimise potential
confounder effects related to using health practitioners with varying qualifications,
clinical experience and expertise. A total of 8 GPs in 9 locations around metropolitan
Melbourne and regional Victoria were involved (Table
1). The GPs had an average of 33.3 years of clinical practice and 19.6 years of medical
acupuncture experience. None had less than 10 years acupuncture experience.

Table 1.Descriptive characteristics of the general practitioners who provided acupuncture
treatment

The GPs attended a four-hour training session run by an investigator (IR) who is an
experienced medical acupuncturist, to standardise all aspects of the treatment protocol.
This same investigator maintained regular contact with the GPs throughout the trial
to answer any treatment-related questions and ensure compliance. Each GP was provided
with a detailed treatment manual describing administration of the acupuncture interventions
as well as the trial protocol. GPs were supplied with a pre-coded laser machine (custom-designed
to deliver both real and sham laser) and standardized needles required for administering
the acupuncture interventions.

Acupuncture treatments (approximately 20 minutes in duration) were administered once
or twice weekly (at the GP’s discretion) in the GP’s rooms for 12 weeks, with a minimum
of 8 and a maximum of 12 treatments delivered. Participants did not pay for treatment
and the treating GPs were reimbursed for their time on a per patient basis.

The treatment protocol permitted the GPs to treat participants as they would treat
patients in their normal practice. They were allowed to select from a standardized
set of acupuncture points around the knee, as well as distal points on the intervention
side (Table
2). Other points could be used at the GP’s discretion depending on the cause(s) and
site of the pain evident at clinical examination. These included points indicated
by Traditional Chinese Medicine diagnoses in relation to Zang-Fu organ dysfunction,
associated meridian and deep channel connections and ear points. Because of varying
participant sensitivity, the initial treatment session permitted a maximum of six
points in total, including four points on the study limb and two other points chosen
as per protocol. In subsequent treatment sessions, further points were added as clinically
indicated by participant response to treatment, as well as local tenderness, muscle
tightness and/or swelling. Over subsequent treatments, acupuncture points were varied
according to changes in participant symptoms and point reactivity. The 12-week treatment
period allowed for patient attendance flexibility (a break of up to four weeks between
visits was deemed acceptable for participants going away on holidays etc.), as well
as for strong acupuncture responders to have several days settling time as necessary.
Visits were scheduled twice per week if necessary, but weekly visits were generally
recommended. Treatment was considered complete when pain and function had returned
to normal, however a minimum of 8 treatments was required. Laser acupuncture interventions
were administered with the patient positioned either supine or sitting over the edge
of the treatment couch. Treating GPs completed standardized treatment notes after
each acupuncture session. Information recorded included the acupuncture points treated
and any adverse events reported by the patient from the previous session.

Table 2.Framework of acupuncture points that could be selected by general practitioners when
administering acupuncture treatments (laser and needles)

Needle acupuncture

Patients randomised to the needle acupuncture treatment underwent treatment lying
down with needles inserted at the selected acupuncture points. Single-use Sierin needles
(0.25x40mm) were used. The needles were inserted and left in place with the participant
to rest. Needles were disposed of into a bedside sharps container at the completion
of treatment.

Laser and placebo laser acupuncture

Laser acupuncture was administered at the selected acupuncture points using a Acupak
P/L (Melbourne) laser machine that was specially manufactured for use in this trial
[24]. The laser machines were standard Class 3B laser devices that are licensed by the
Australian Therapeutic Goods Association with an output of 10 mW. Energy output was
0.2 J per acupuncture point. Laser strength was checked by the manufacturer (a biomedical
engineer) at study commencement, halfway through the study and will be repeated at
study completion. Laser strength testing is a routine procedure in laser manufacture
and maintenance and is done with a standard laser testing device. The trial laser
machine had a small red non-laser light source arising from inside the probe tip that
lit up when the probe was in both treatment mode and sham mode (no output). This acted
as a decoy to the treatment beam, which is invisible. Therefore, neither the treating
GP nor the participant could detect any difference between the real or sham laser
treatment being applied. The trial laser machines were programmed by the manufacturer.
At each treatment session, the GP typed the participant’s study code into the keypad
of the machine, and the machine automatically delivered either laser acupuncture (ie
laser output) or sham laser acupuncture (ie no laser output) according to the programmed
randomisation schedule.

Outcome measures

Table
3 summarises the range of measures that are being collected as part of this study.
The majority of outcomes are measured at baseline, 12 weeks and 12 months in all participants
(irrespective of group allocation). All outcomes are collected via self-report questionnaire
and mailed back to the investigators.

Self-reported pain and physical function

The primary pain outcome is average overall knee pain over the past week. This is
assessed using an 11-point NRS with terminal descriptors of “no pain” and “worst pain
possible”. Similar scales are also being used to assess average pain on standing and
on walking over the past week as secondary outcomes. Pain is also assessed, along
with physical function, using the disease-specific WOMAC Osteoarthritis Index
[31]. The physical function subscale, which comprises 17 questions, is the primary outcome
measure for self-reported physical function. A secondary measure of physical function
is a NRS assessing average restriction to daily activities over the past week with
terminal descriptors of “no restriction” and “maximum restriction possible”.

At the 12 week and 12 month assessments, participants rate their perceived change
in a) pain; b) physical function and; c) overall, compared to baseline on a five-point
ordinal scale (1-much worse to 5-much better). Scales of this kind are frequently
used as an external criterion for comparison with changes in scores of other outcomes
[32]. Measuring participant-perceived change using a rating of change scale has been shown
to be a clinically relevant and stable concept for interpreting truly meaningful improvements
from the individual perspective
[33].

Health-related quality of life

Health-related quality of life is measured using the Assessment of Quality of Life
instrument version two (AQoL II). The AQoL II has 20 questions that cover six dimensions
of health-related quality of life including independent living, social relationships,
physical senses, coping, pain and psychological wellbeing. The AQoL has strong psychometric
properties and is more responsive than other more widely used scales
[34,35]. It produces a single utility index that ranges from −0.04 (worst possible health-related
quality of life) to 1.00 (full health-related quality of life).

The 12-item Short Form Health Survey (SF-12) is also being used to measure health-related
quality of life
[36]. The SF-12 is a self-administered questionnaire that was designed to measure patient
outcomes in medical practice and clinical research and to evaluate the effectiveness
of health interventions. The 12 questions in the SF-12 measure an individual’s perceived
health across eight domains: physical functioning; role limitations because of physical
health problems; bodily pain; general health perceptions; energy/fatigue; social functioning;
role limitations because of emotional problems; and general mental health. The SF-12
is scored so that a high score indicates better functioning. Scoring algorithms are
applied to individual item responses to produce the composite Physical Component Summary
(PCS) and Mental Component Summary (MCS) scores. The PCS and MCS scores have a range
of 0 to 100 and were designed to have a mean score of 50 and a standard deviation
of 10; scores greater than 50 represent above average health status.

Psychosocial measures

A range of psychosocial measures are being collected in order to evaluate whether
psychosocial parameters are associated with changes in pain, physical function and
health-related quality of life observed with acupuncture.

i) Arthritis Self-Efficacy Scale is used to measure self-efficacy. It has three subscales
that assess self-efficacy for control of pain management (5 questions), physical function
(9 questions) and other arthritis symptoms (6 questions). Each question is rated on
a 10-point NRS from 1 (“very uncertain”) to 10 (“very certain”). Prior studies have
supported both the reliability and validity of this scale
[37].

iii) Medical Outcomes Study (MOS) Social Support Survey is used to measure the perceived
social support available to an individual. It comprises six questions that ask respondents
to indicate how often each of six different types of support is available to them.
Responses are scored on a five-point scale ranging from “all of the time” to “none
of the time”. This measure of social support has been shown to have adequate validity
and reliability
[39].

iv) Patient Health Questionnaire (PHQ) is a self-administered version of the PRIME-MD
diagnostic instrument for common mental disorders
[40] . This trial is utilizing the PHQ-9
[41], which is the depression module that scores each of the 9 DSM-IV criteria
[42] as “0” (not at all) to “3” (nearly every day).

v) Revised Health Hardiness Inventory comprises 24 items and is used to measure health
hardiness (control, commitment, and challenge) in individuals with actual health problems.
Respondents indicate on a 5-point scale the degree to which they agree with the statement,
ranging from “strongly disagree” to “strongly agree”. This questionnaire has adequate
psychometric properties, and is a reliable and useful instrument to assess perspectives
towards one’s own health
[43].

Physical activity levels

Habitual physical activity is measured using the Physical Activity Scale for the Elderly
(PASE), a self-report questionnaire that has been shown to be reliable, valid and
sensitive to change in people with knee OA
[44,45]. It records both the level and type of recreational and occupational physical activity
undertaken by participants over the previous week. The PASE was developed and validated
in samples of older adults (age 55+ years)
[46].

Use of health care, home assistance and work absences

Information on health care use (e.g. visits to hospitals, medical practitioners, other
health professionals, use of investigative procedures, prescription and non-prescription
drugs) and the need for paid and/or unpaid home assistance over the previous four
weeks will be collected via a log-book at baseline, 12 weeks and 12 months. Participants
are also asked to record any absences from paid employment (if applicable) and/or
unpaid work (eg household duties, caring for family/friends) because of their health.
The log-book utilises a checklist format to minimize respondent burden and to ensure
high quality data is obtained with minimal data loss.

Adverse events

Adverse events were monitored via open-ended questioning by the acupuncturist at each
treatment session and recorded in the treatment notes. In addition, participants receiving
acupuncture treatment were asked at 12 weeks whether they experienced any adverse
effects of treatment via open-ended questioning.

Treatment session attendance

Participant adherence was measured by recording the number of treatment sessions attended
(out of a maximum number of 12) in the GP treatment notes.

Sample size calculations

Our primary endpoints are average overall knee pain measured on a NRS and physical
function measured via WOMAC at 12 weeks. The minimum clinically important difference
to be detected in OA trials is a change in pain of 1.8 units (on NRS)
[47] and a change of 6 physical function units on the WOMAC (out of 68)
[48]. Calculations are based on an analysis of covariance (ANCOVA) adjusting for baseline
of the outcome variable, and assume a between-patient standard deviation of 3.0 units
for pain and 12.0 units for WOMAC
[49]. Sample size calculations for our particular study design need to take into account
four aspects: clustering effects resulting from treatment of patients by the same
therapist for comparisons with the control arm (hypothesis H2); dilution of the treatment
effect resulting from the Zelen design
[50]; precision gain from baseline adjustment; and loss to followup. Initially assuming
no clustering effects and a regular two-arm parallel RCT design with complete followup,
33 patients per arm would be required to detect the above differences in pain and
function with 80% power at a two-sided 5% significance level, using ANCOVA with assumed
baseline to 12 week correlations of 0.50 for pain and 0.70 for function
[49]. Adopting a conservative intra-therapist correlation of 0.10 inflates the sample
size to 40 patients per arm across a total of 10 therapists. Assuming a conservative
15% non-consent rate for patients randomised to any of the three treatment arms increases
the sample size by 1/(1–0.15)2 = 38%, and finally, allowing for 15% loss to followup, inflates the total sample
size to 66 patients per arm, which we round up to 70 per arm, or 280 patients in total.
Assessment of hypotheses H1 and H3 involve within-therapist comparisons only and therefore
the precision loss from clustering by therapist does not apply, yielding greater power
(90%) for these comparisons.

Statistical analyses

The primary analysis of the data will be undertaken using the principle of intention-to-treat
with all randomised patients included in the analyses. Demographic and clinical characteristics,
as well as baseline data, will be presented to assess the baseline comparability of
the intervention groups. Descriptive statistics will be presented for each group as
the mean change (standard deviation, 95% confidence intervals) in the outcomes from
baseline to each time point. Differences in mean change from baseline to each time
point will be compared between groups using random effects linear regression modelling
adjusting for baseline levels of the outcome measure and using the treating therapists
as random effects to account for clustering of outcomes by therapists. Model assumptions
will be checked by standard diagnostic plots. Improvement between acupuncture groups
(based on the perceived ratings of change) will be compared using logistic regression
with random effects as above and presented as odds ratios with 95% confidence intervals.
Multiple imputation methodology will be employed to account for missing data
[51]. No statistical adjustment will be made for multiple testing. All tests will be two
sided and carried out at the 5% level of significance.

As part of the secondary analyses of the primary outcomes at 12 weeks and 12 months,
we plan to conduct a separate analysis to estimate the effect of treatment in the
hypothetical scenario of full adherence to the randomised treatment intervention.
Analytical methods for this will utilise instrumental variables methodology involving
two stage least squares estimation
[52].

Economic evaluation

The economic evaluation will be conducted from the perspective of the Australian health
care system and the individual patient. Standard methods of economic evaluation alongside
a clinical trial will be used to evaluate the differences in resource use and health
outcomes at the end of treatment and at 12 months. The primary economic evaluation
will take the form of a cost effectiveness study with a range of outcome measures
including the incremental cost per extra person with a clinically significant improvement
in pain and function and per extra quality adjusted life years (QALYs) for laser acupuncture
compared to either sham or needle acupuncture. The difference in QALYs will be calculated
in the primary analysis as the difference in the area under the curve for AQoL scores
over the duration of 12 months. Differences in mean change from baseline for the AQoL
to each time point will be weighted by the time from baseline using generalised linear
regression modelling adjusting for baseline levels of the AQoL to construct QALYs,
and then compared between groups. Differences in the mean cost between groups will
be calculated using generalised linear regression modelling. Incremental cost per
QALY will be calculated as the ratio of the difference in mean cost to the difference
in mean QALYs with 95% confidence intervals calculated using Fieller's theorem.

Timelines

The application for project funding was successful in December 2008 and funding commenced
in August 2009. Ethics approval was obtained from the Human Research Ethics Committee
of the University of Melbourne in July 2009. Recruitment commenced in February 2010
and was completed in December 2011. The trial is due for completion in December 2012
when all participants will have completed 12-month follow-up.

Discussion

This paper has presented the theoretical rationale, as well as the protocol, for an
ongoing Zelen design RCT that is testing the efficacy of a combined Western and Traditional
Chinese Medicine style of acupuncture for managing chronic knee pain and disability
symptoms in older people. The findings of this study will help determine whether laser
and/or needle acupuncture are efficacious in relieving knee pain and/or improving
physical function. This study will also determine whether effects of acupuncture can
be maintained over the longer term, and whether psychosocial factors influence treatment
outcomes. Importantly, the use of the Zelen design will minimize the bias typically
encountered in traditionally designed RCTs where participant expectations may influence
study outcomes.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

RSH, PM, KMC and KLB conceived the project and PM is leading the co-ordination of
the trial. RSH, PM, KMC, MP, IR, PR, AF, AH and KLB developed the protocol and procured
the project funding. IR and MP designed the acupuncture program and IR trained the
GPs. AF performed the sample size calculations and designed the statistical analyses.
AH is leading the collection and analysis of the cost-effectiveness data. MK recruits
and screens the participants and performs data entry, while KN randomises participants
to groups and is the liaison for the treating GP’s and participants. RSH and KLB wrote
the first draft of the manuscript. RSH wrote the final draft of this manuscript. All
authors participated in the trial design, provided feedback on drafts of this paper
and read and approved the final manuscript.

Acknowledgements

This trial is being funded by the National Health and Medical Research Council (Project
#566783). None of the funders have any role in the study other than to provide funding.
KLB is funded in part by an Australian Research Council Future Fellowship. MP was
funded by a Primary Health Care Research Evaluation Development fellowship. PM is
funded in part by an NHMRC Practitioner Fellowship. The Study GPs providing the acupuncture
treatments are Dr Ian Relf, Dr Paul Ghaie, Dr Sandra Martin, Dr Danny Traum, Dr Paul
Coughlan, Dr Robert Meyer, Dr Malcolm Macdonald and Dr Tim Denton. We wish to acknowledge
Dr Roberta Chow for her valuable advice regarding the treatment protocols.

Whitfield K, Buchbinder R, Segal L, Osborne RH: Parsimonious and efficient assessment of health-related quality of life in osteoarthritis
research: validation of the Assessment of Quality of Life (AQoL) instrument.